Hemodialysis can be an outpatient or inpatient therapy.
Routine hemodialysis is conducted in a dialysis outpatient
facility, either a purpose built room in a hospital or a dedicated, stand alone clinic.
Less frequently hemodialysis is done at home.
Dialysis treatments in a clinic are initiated and managed by
specialized staff made up of nurses and technicians; dialysis
treatments at home can be self initiated and managed or done
jointly with the assistance of a trained helper who is usually a
family member.[1]

Principle

Semipermeable membrane

The principle of hemodialysis is the same as other methods of dialysis; it involves diffusion of solutes across
a semipermeable membrane. Hemodialysis utilizes counter current flow, where the dialysate
is flowing in the opposite direction to blood flow in the extracorporeal circuit. Counter-current
flow maintains the concentration gradient across the membrane at a
maximum and increases the efficiency of the dialysis.

Fluid removal (ultrafiltration) is achieved by
altering the hydrostatic
pressure of the dialysate compartment, causing free water and
some dissolved solutes to move across the membrane along a created
pressure gradient.

The dialysis solution that is used is a sterilized solution of
mineral ions. Urea and other waste
products, potassium, and
phosphate diffuse into
the dialysis solution. However, concentrations of sodium and chloride are similar to those of
normal plasma to
prevent loss. Sodium bicarbonate is added in a
higher concentration than plasma to correct blood acidity. A small
amount of glucose is also commonly used.

Note that this is a different process to the related technique
of hemofiltration.

History

Many have played a role in developing dialysis as a practical
treatment for renal failure, starting with Thomas Graham of Glasgow, who first
presented the principles of solute transport across a semipermeable
membrane in 1854.[2] The
artificial kidney was first developed by Abel, Rountree and Turner in 1913,[3], the
first hemodialysis in a human being was by Hass (February 28, 1924)[4] and the
artificial kidney was developed into a clinically useful apparatus
by Kolff in 1943 - 1945.[5] This
research showed that life could be prolonged in patients dying of
renal
failure.

Dr. Willem Kolff was the first to
construct a working dialyzer in 1943. The first successfully
treated patient was a 67-year-old woman in uremic coma who regained consciousness after 11
hours of hemodialysis with Kolff’s dialyzer in 1945. At the time of
its creation, Kolff’s goal was to provide life support during
recovery from acute renal failure. After World War II ended, Kolff donated the five
dialyzers he had made to hospitals around the world, including Mount Sinai Hospital, New
York. Kolff gave a set of blueprints for his hemodialysis
machine to George Thorn at the Peter Bent
Brigham Hospital in Boston. This led to the manufacture of the next
generation of Kolff’s dialyzer, a stainless steel Kolff-Brigham dialysis
machine.

By the 1950s, Willem Kolff’s invention of the dialyzer was used
for acute renal failure, but it was not seen as a viable treatment
for patients with stage 5 chronic kidney disease
(CKD). At the time, doctors believed it was impossible for patients
to have dialysis indefinitely for two reasons. First, they thought
no man-made device could replace the function of kidneys over the
long term. In addition, a patient undergoing dialysis suffered from
damaged veins and arteries, so that after several treatments, it
became difficult to find a vessel to access the patient’s
blood.

Dr. Nils
Alwall: The original Kolff kidney was not very useful
clinically, because it did not allow for removal of excess fluid.
Dr. Nils Alwall [6] encased
a modified version of this kidney inside a stainless steel
canister, to which a negative pressure could be applied, in this
way effecting the first truly practical application of
hemodialysis, which was done in 1946 at the University of Lund. Alwall also was
arguably the inventor of the arteriovenous shunt for dialysis. He
reported this first in 1948 where he used such an arteriovenous
shunt in rabbits. Subsequently he used such shunts, made of glass,
as well as his canister-enclosed dialyzer, to treat 1500 patients
in renal failure between 1946 and 1960, as reported to the First
International Congress of Nephrology held in Evian in September
1960. Alwall was appointed to a newly-created Chair of Nephrology
at the University of Lund in 1957. Subsequently, he collaborated
with Swedish businessman Holger Crafoord to found one of the key
companies that would manufacture dialysis equipment in the past 50
years, Gambro, Inc. The early
history of dialysis has been reviewed by Stanley Shaldon [7].

Dr. Belding H.
Scribner working with a surgeon, Dr. Wayne Quinton,
modified the glass shunts used by Alwall by making them from Teflon. Another key improvement
was to connect them to a short piece of silicone elastomer tubing.
This formed the basis of the so-called Scribner shunt,
perhaps more properly called the Quinton-Scribner shunt. After
treatment, the circulatory access would be kept open by connecting
the two tubes outside the body using a small U-shaped Teflon tube,
which would shunt the blood from the tube in the artery back to the
tube in the vein [8].

In 1962, Scribner started the world’s first outpatient dialysis
facility, the Seattle Artificial Kidney Center, later renamed the
Northwest Kidney Centers.
Immediately the problem arose of who should be given dialysis,
since demand far exceeded the capacity of the six dialysis machines
at the center. Scribner decided that the decision about who would
receive dialysis and who wouldn’t, would not be made by him.
Instead, the choices would be made by an anonymous committee, which
could be viewed as one of the first bioethics committees.

For a detailed history of successful and unsuccessful attempts
at dialysis, including pioneers such as Abel and Roundtree, Haas,
and Necheles, see this review by Kjellstrand [9].

Prescription

A prescription for dialysis by a nephrologist (a
medical kidney specialist) will specify various parameters for a
dialysis treatment. These include frequency (how many treatments
per week), length of each treatment, and the blood and dialysis
solution flow rates, as well as the size of the dialyzer. The
composition of the dialysis solution is also sometimes adjusted in
terms of its sodium and potassium and bicarbonate levels. In
general, the larger the body size of an individual, the more
dialysis he/she will need. In the North America and UK, 3-4 hour
treatments (sometimes up to 5 hours for larger patients) given 3
times a week are typical. Twice-a-week sessions are limited to
patients who have a substantial residual kidney function. Four
sessions per week are often prescribed for larger patients, as well
as patients who have trouble with fluid overload. Finally, there is
growing interest in short daily home hemodialysis, which
is 1.5 - 4 hr sessions given 5-7 times per week, usually at home.
There also is interest in nocturnal dialysis, which involves
dialyzing a patient, usually at home, for 8–10 hours per night, 3-6
nights per week. Nocturnal in-center dialysis, 3-4 times per week
is also offered at a handful of dialysis units in the United States.

Side effects and
complications

Hemodialysis often involves fluid removal (through ultrafiltration), because most
patients with renal
failure pass little or no urine. Side effects caused by
removing too much fluid and/or removing fluid too rapidly include
low blood
pressure, fatigue, chest
pains, leg-cramps, nausea and
headaches. These symptoms can occur during
the treatment and can persist post treatment; they are sometimes
collectively referred to as the dialysis hangover or dialysis
washout. The severity of these symptoms is usually proportionate to
the amount and speed of fluid removal. However, the impact of a
given amount or rate of fluid removal can vary greatly from person
to person and day to day. These side effects can be avoided and/or
their severity lessened by limiting fluid intake between treatments
or increasing the dose of dialysis e.g. dialyzing more often or
longer per treatment than the standard three times a week, 3–4
hours per treatment schedule.

Since hemodialysis requires access to the circulatory system,
patients undergoing hemodialysis may expose their circulatory
system to microbes, which can lead to sepsis, an infection affecting
the heart valves (endocarditis) or an infection affecting
the bones (osteomyelitis). The risk of infection
varies depending on the type of access used (see below). Bleeding
may also occur, again the risk varies depending on the type of
access used. Infections can be minimized by strictly adhering to infection
control best practices.

Heparin is the most
commonly used anticoagulant in hemodialysis, as it is generally
well tolerated and can be quickly reversed with protamine
sulfate. Heparin allergy can infrequently be a problem and can
cause a low platelet count. In such patients, alternative
anticoagulants can be used. In patients at high risk of bleeding,
dialysis can be done without anticoagulation.

First Use Syndrome is a rare but severe anaphylactic reaction to the artificial
kidney. Its symptoms include sneezing, wheezing, shortness of
breath, back pain, chest pain, or sudden death. It can be caused by
residual sterilant in the artificial kidney or the material of the
membrane itself. In recent years, the incidence of First Use
Syndrome has decreased, due to an increased use of gamma
irradiation, steam sterilization, or electron-beam radiation
instead of chemical sterilants, and the development of new
semipermeable membranes of higher biocompatibility. New methods of
processing previously acceptable components of dialysis must always
been considered. For example, in 2008, a series of first-use type
or reactions, including deaths occurred due to heparin contaminated
during the manufacturing process with oversulfated chondroitin
sulfate. [10]

Longterm complications of hemodialysis include amyloidosis, neuropathy and various forms of heart disease.
Increasing the frequency and length of treatments have been shown
to improve fluid overload and enlargement of the heart that is
commonly seen in such patients.[11][12]

Listed below are specific complications associated with
different types of hemodialysis access.

Access

In hemodialysis, three primary methods are used to gain access
to the blood: an intravenous catheter, an arteriovenous (AV)
fistula and a synthetic graft. The type of access is influenced by
factors such as the expected time course of a patient's renal
failure and the condition of his or her vasculature. Patients may
have multiple accesses, usually because an AV fistula or graft is
maturing and a catheter is still being used.

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Catheter

Catheter access, sometimes called a CVC (Central Venous Catheter),
consists of a plastic catheter with two lumens (or occasionally two
separate catheters) which is inserted into a large vein (usually
the vena
cava, via the internal jugular vein or the femoral vein) to
allow large flows of blood to be withdrawn from one lumen, to enter
the dialysis circuit, and to be returned via the other lumen.
However, blood flow is almost always less than that of a well
functioning fistula or graft.

Catheters are usually found in two general varieties, tunnelled
and non-tunnelled.

Non-tunnelled catheter access is for short-term
access (up to about 10 days, but often for one dialysis session
only), and the catheter emerges from the skin at the site of entry
into the vein.

Tunnelled catheter access involves a longer
catheter, which is tunnelled under the skin from the point of
insertion in the vein to an exit site some distance away. It is
usually placed in the internal jugular vein in the neck and the
exit site is usually on the chest wall. The tunnel acts as a
barrier to invading microbes, and as such, tunnelled catheters are
designed for short- to medium-term access (weeks to months only),
because infection is still a frequent problem.

Aside from infection, venous stenosis is another serious problem with
catheter access. The catheter is a foreign body in the vein and
often provokes an inflammatory reaction in the vein wall. This
results in scarring and narrowing of the vein, often
to the point of occlusion. This can cause problems with severe
venous congestion in the area drained by the vein and may also
render the vein, and the veins drained by it, useless for creating
a fistula or graft at a later date. Patients on long-term
hemodialysis can literally 'run out' of access, so this can be a
fatal problem.

Catheter access is usually used for rapid access for immediate
dialysis, for tunnelled access in patients who are deemed likely to
recover from acute renal
failure, and for patients with end-stage renal failure who are either
waiting for alternative access to mature or who are unable to have
alternative access.

Catheter access is often popular with patients, because
attachment to the dialysis machine doesn't require needles.
However, the serious risks of catheter access noted above mean that
such access should be contemplated only as a long-term solution in
the most desperate access situation.

AV
fistula

A radiocephalic fistula.

AV (arteriovenous) fistulas are recognized as the preferred
access method. To create a fistula, a vascular surgeon
joins an artery and a vein together through anastomosis. Since this
bypasses the capillaries, blood flows rapidly through
the fistula. One can feel this by placing one's finger over a
mature fistula. This is called feeling for "thrill" and produces a
distinct 'buzzing' feeling over the fistula. One can also listen
through a stethoscope for the sound of the blood
"whooshing" through the fistula, a sound called bruit.

Fistulas are usually created in the nondominant arm and may be
situated on the hand (the 'snuffbox' fistula'), the forearm (usually a
radiocephalic fistula, or so-called Brescia-Cimino fistula,
in which the radial
artery is anastomosed to the cephalic vein), or the elbow (usually a
brachiocephalic fistula, where the brachial artery is anastomosed to the
cephalic vein).
A fistula will take a number of weeks to mature, on average perhaps
4–6 weeks. During treatment, two needles are inserted into the
fistula, one to draw blood and one to return it.

The advantages of the AV fistula use are lower infection rates,
because no foreign material is involved in their formation, higher
blood flow rates (which translates to more effective dialysis), and
a lower incidence of thrombosis. The complications are few, but
if a fistula has a very high blood flow and the vasculature that
supplies the rest of the limb is poor, a steal syndrome can
occur, where blood entering the limb is drawn into the fistula and
returned to the general circulation without entering the limb's
capillaries. This results in cold extremities of that limb,
cramping pains, and, if severe, tissue damage. One long-term
complication of an AV fistula can be the development of an
aneurysm, a bulging in the wall of the vein where it is weakened by
the repeated insertion of needles over time. To a large extent the
risk of developing an aneurysm can be reduced by careful needling
technique. Aneurysms may necessitate corrective surgery and may
shorten the useful life of a fistula. To prevent damage to the
fistula and aneurysm or pseudoaneurysm formation, it is recommended
that the needle be inserted at different points in a rotating
fashion. Another approach is to cannulate the fistula with a
blunted needle, in exactly the same place. This is called a
'buttonhole' approach. Often two or three buttonhole places are
available on a given fistula. This also can prolong fistula life
and help prevent damage to the fistula.

AV graft

An arteriovenous graft.

AV (arteriovenous) grafts are much like fistulas in most
respects, except that an artificial vessel is used to join the
artery and vein. The graft usually is made of a synthetic material,
often PTFE, but sometimes chemically
treated, sterilized veins from animals are used. Grafts are
inserted when the patient's native vasculature does not permit a
fistula. They mature faster than fistulas, and may be ready for use
several weeks after formation (some newer grafts may be used even
sooner). However, AV grafts are at high risk to develop narrowing,
especially in the vein just downstream from where the graft has
been sewn to the vein. Narrowing often leads to clotting or
thrombosis. As foreign material, they are at greater risk for
becoming infected. More options for sites to place a graft are
available, because the graft can be made quite long. Thus a graft
can be placed in the thigh or even the neck (the 'necklace
graft').

Fistula
First project

AV fistulas have a much better access patency and survival than
do venous catheters or grafts. They also produce better patient
survival and have far fewer complications compared to grafts or
venous catheters. For this reason, the Centers for Medicare &
Medicaid (CMS) has set up a Fistula First Initiative [13],
whose goal is to increase the use of AV fistulas in dialysis
patients.

Equipment

Schematic of a hemodialysis circuit

The hemodialysis machine pumps the patient's blood and the
dialysate through the dialyzer. The newest dialysis machines on the
market are highly computerized and continuously monitor an array of
safety-critical parameters, including blood and dialysate flow
rates; dialysis solution conductivity, temperature, and pH; and
analysis of the dialysate for evidence of blood leakage or presence
of air. Any reading that is out of normal range triggers an audible
alarm to alert the patient-care technician who is monitoring the
patient. Manufacturers of dialysis machines include companies such
as Fresenius, Gambro, Baxter, B. Braun, NxStage and
Bellco.

Water
system

A hemodialysis unit's dialysate solution tanks

An extensive water purification system is
absolutely critical for hemodialysis. Since dialysis patients are
exposed to vast quantities of water, which is mixed with dialysate
concentrate to form the dialysate, even trace mineral contaminants
or bacterial endotoxins can filter into the patient's
blood. Because the damaged kidneys cannot perform their intended
function of removing impurities, ions introduced into the
bloodstream via water can build up to hazardous levels, causing
numerous symptoms or death.
Aluminum, chloramine, fluoride, copper, and zinc, as well as
bacterial fragments and endotoxins, have all caused problems in
this regard.

For this reason, water used in hemodialysis is carefully
purified before use. Initially it is filtered and
temperature-adjusted and its pH is corrected by adding an acid or
base. Then it is softened. Next the water is run through a tank
containing activated charcoal to adsorb organic contaminants. Primary
purification is then done by forcing water through a membrane with
very tiny pores, a so-called reverse osmosis membrane. This lets the
water pass, but holds back even very small solutes such as
electrolytes. Final removal of leftover electrolytes is done by
passing the water through a tank with ion-exchange resins, which
remove any leftover anions or cations and replace them with
hydroxyl and hydrogen molecules, respectively, leaving ultrapure
water.

Even this degree of water purification may be insufficient. The
trend lately is to pass this final purified water (after mixing
with dialysate concentrate) through a dialyzer membrane. This
provides another layer of protection by removing impurities,
especially those of bacterial origin, that may have accumulated in
the water after its passage through the original water purification
system.

Once purified water is mixed with dialysate concentrate, its
conductivity increases, since water that contains charged ions
conducts electricity. During dialysis, the conductivity of dialysis
solution is continuously monitored to ensure that the water and
dialysate concentrate are being mixed in the proper proportions.
Both excessively concentrated dialysis solution and excessively
dilute solution can cause severe clinical problems.

Dialyzer

The dialyzer is the piece of equipment that actually filters the
blood. Almost all dialyzers in use today are of the hollow-fiber
variety. A cylindrical bundle of hollow fibers, whose walls are
composed of semi-permeable membrane, is anchored at each end into
potting compound (a sort of glue). This assembly is then put into a
clear plastic cylindrical shell with four openings. One opening or
blood port at each end of the cylinder communicates with each end
of the bundle of hollow fibers. This forms the "blood compartment"
of the dialyzer. Two other ports are cut into the side of the
cylinder. These communicate with the space around the hollow
fibers, the "dialysate compartment." Blood is pumped via the blood
ports through this bundle of very thin capillary-like tubes, and the dialysate is
pumped through the space surrounding the fibers. Pressure gradients
are applied when necessary to move fluid from the blood to the
dialysate compartment.

Membrane and
flux

Dialyzer membranes come with different pore sizes. Those with
smaller pore size are called "low-flux" and those with larger pore
sizes are called "high-flux." Some larger molecules, such as
beta-2-microglobulin, are not removed at all with low-flux
dialyzers; lately, the trend has been to use high-flux dialyzers.
However, such dialyzers require newer dialysis machines and
high-quality dialysis solution to control the rate of fluid removal
properly and to prevent backflow of dialysis solution impurities
into the patient through the membrane.

Dialyzer membranes used to be made primarily of cellulose
(derived from cotton linter). The surface of such membranes was not
very biocompatible, because exposed hydroxyl groups would activate
complement in the blood passing by
the membrane. Therefore, the basic, "unsubstituted" cellulose
membrane was modified. One change was to cover these hydroxyl
groups with acetate groups (cellulose acetate); another was to mix
in some compounds that would inhibit complement activation at the
membrane surface (modified cellulose). The original "unsubstituted
cellulose" membranes are no longer in wide use, whereas cellulose
acetate and modified cellulose dialyzers are still used. Cellulosic
membranes can be made in either low-flux or high-flux
configuration, depending on their pore size.

Another group of membranes is made from synthetic materials,
using polymers such as
polyarylethersulfone, polyamide, polyvinylpyrrolidone,
polycarbonate, and polyacrylonitrile. These synthetic membranes
activate complement to a lesser degree than unsubstituted cellulose
membranes. Synthetic membranes can be made in either low- or
high-flux configuration, but most are high-flux.

Nanotechnology is being used in some of the most recent
high-flux membranes to create a uniform pore size. The goal of
high-flux membranes is to pass relatively large molecules such as
beta-2-microglobulin (MW 11,600 daltons), but not to pass albumin
(MW ~66,400 daltons). Every membrane has pores in a range of sizes.
As pore size increases, some high-flux dialyzers begin to let
albumin pass out of the blood into the dialysate. This is thought
to be undesirable, although one school of thought holds that
removing some albumin may be beneficial in terms of removing
protein-bound uremic toxins.

Membrane flux and
outcome

Whether using a high-flux dialyzer improves patient outcomes is
somewhat controversial, but several important studies have
suggested that it has clinical benefits. The NIH-funded HEMO trial
compared survival and hospitalizations in patients randomized to
dialysis with either low-flux or high-flux membranes. Although the
primary outcome (all-cause mortality) did not reach statistical
significance in the group randomized to use high-flux membranes,
several secondary outcomes were better in the high-flux group [14][15]. A
recent Cochrane analysis concluded that benefit of membrane choice
on outcomes has not yet been demonstrated [16]. A
collaborative randomized trial from Europe, the MPO (Membrane
Permeabilities Outcomes) study, [17]
comparing mortality in patients just starting dialysis using either
high-flux or low-flux membranes, found a nonsignificant trend to
improved survival in those using high-flux membranes, and a
survival benefit in patients with lower serum albumin levels or in
diabetics.

Membrane
flux and beta-2-microglobulin amyloidosis

High-flux dialysis membranes and/or intermittent on-line
hemodiafiltration (IHDF) may also be beneficial in reducing
complications of beta-2-microglobulin accumulation. Because
beta-2-microglobulin is a large molecule, with a molecular weight
of about 11,600 daltons, it does not pass at all through low-flux
dialysis membranes. Beta-2-M is removed with high-flux dialysis,
but is removed even more efficiently with IHDF. After several years
(usually at least 5-7), patients on hemodialysis begin to develop
complications from beta-2-M accumulation, including carpal tunnel
syndrome, bone cysts, and deposits of this amyloid in joints and
other tissues. Beta-2-M amyloidosis can cause very serious
complications, including a spondylarthropathy, and often is
associated with shoulder joint problems. Observational studies from
Europe and Japan have suggested that using high-flux membranes in
dialysis mode, or IHDF, reduces beta-2-M complications in
comparison to regular dialysis using a low-flux membrane. [18][19][20][21][22]

Dialyzer size and
efficiency

Dialyzers come in many different sizes. A larger dialyzer with a
larger membrane area (A) will usually remove more solutes than a
smaller dialyzer, especially at high blood flow rates. This also
depends on the membrane permeability coefficient
K0 for the solute in question. So dialyzer
efficiency is usually expressed as the K0A -
the product of permeability coefficient and area. Most dialyzers
have membrane surface areas of 0.8 to 2.2 square meters, and values
of K0A ranging from about 500 to 1500 mL/min.
K0A, expressed in mL/min, can be thought of as
the maximum clearance of a dialyzer at very high blood and
dialysate flow rates.

Reuse of
dialyzers

The dialyzer may either be discarded after each treatment or be
reused. Reuse requires an extensive procedure of high-level
disinfection. Reused dialyzers are not shared between patients.
There was an initial controversy about whether reusing dialyzers
worsened patient outcomes. The consensus today is that reuse of
dialyzers, done carefully and properly, produces similar outcomes
to single use of dialyzers [23].

^
Shaldon S. Development of Hemodialysis, From Access to Machine
(presentation given during a symposium entitled: Excellence in
Dialysis: Update in Nephrology; Karachi, Pakistan. October, 2002,
as archived on HDCN